Over the past decade, several groups have demonstrated a blunting in stimulant-induced dopamine (DA) release at the level of the striatum as a whole and ventral striatum (which includes the limbic-related nucleus accumbens) in alcohol dependent subjects (Martinez et al 2005;Volkow et al 2007). These findings have suggested an abnormal regulation of DA release following stimulant administration in the brain of patients with alcohol dependence. An important limitation of these studies is the fact that measurements of D2 receptors and amphetamine-induced DA release were restricted to the striatum because the ligands used did not provide enough signal to noise ratio to quantify D2 receptors in extrastriatal regions. Given that metabolic PET imaging/fMRI data in alcohol dependence suggests a relationship between pathological activation of the prefrontal cortex and cognitive deficits, which in turn increase the risk for relapse to drugs, it is of extreme interest to understand the regulatory role of DA in this particular region as well. We obtained preliminary evidence using the high D2 receptor affinity PET radiotracer [11C]FLB 457 to measure amphetamine-induced DA release in the cortical regions of interest, including the dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex (MPFC), anterior cingulate cortex (ACC) and medial temporal lobe (MTL, which includes the amygdala and hippocampus). In this application, we propose to use this technique to study amphetamine-induced DA release in the mesolimbic-related immediate reward system (ACC, OFC, MPFC, MTL) and mesocortical-related delayed reward system (DLPFC) in alcoholics and matched controls. Based on current clinical and preclinical evidence, the hypothesis is that amphetamine- induced dopamine release will be elevated in the mesolimbic DA system and blunted in the mesocortical DA system in patients with alcohol dependence as compared with matched controls. In addition, we propose to conduct fMRI experiments during a simple reward task and associate them with the PET findings to understand the functional significance of DA transmission in different cortical regions. The understanding of the cortical DA abnormalities and their functional significance in addictive disorders such as alcoholics will allow for the advancement of novel treatment strategies. PUBLIC HEALTH RELEVANCE In this application, we propose to use PET and fMRI to evaluate the functional significance of DA transmission abnormalities in the cortex of alcoholics.